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Šupuk, Enes, Ghori, Muhammad U., Asare-Addo, Kofi, Laity, Peter R., Panchmatia, Pooja M. and Conway, Barbara R
The influence of salt formation on electrostatic and compression properties of flurbiprofen salts
Original Citation
Šupuk, Enes, Ghori, Muhammad U., Asare-Addo, Kofi, Laity, Peter R., Panchmatia, Pooja M. and Conway, Barbara R (2013) The influence of salt formation on electrostatic and compression properties of flurbiprofen salts. International Journal of Pharmaceutics, 458 (1). pp. 118-127. ISSN 0378-5173
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The Influence of Salt Formation on Electrostatic and Compression Properties of
Flurbiprofen Salts
Enes Šupuk1*, Muhammad U. Ghori1, Kofi Asare-Addo1, Peter R. Laity1, Pooja Panchmatia2,
Barbara R. Conway1
1Pharmacy and Pharmaceutical Sciences, School of Applied Sciences, University of Huddersfield,
Huddersfield, HD1 3DH, UK.
2Chemical and Biological Sciences, School of Applied Sciences, University of Huddersfield, Huddersfield,
HD1 3DH, UK.
* Corresponding Author:
Tel. +44 (0) 1484 472 813
Fax. + (0) 1484 472 182
E-mail address: [email protected] (E. Supuk)
Abstract
Salt formation is an effective method of improving physicochemical properties of acidic and
basic drugs. The selection of a salt form most suitable for drug development requires a well-
designed screening strategy to ensure various issues are addressed in the early development stages.
Triboelectrification of pharmaceutical powders may cause problems during processing such as
segregation of components due to the effects of particle adhesion. However, very little work has
been done on the effect of salt formation on triboelectrification properties. In this paper, salts of
flurbiprofen were prepared by combining the drug with a selection of closely related amine
counterions. The aim of the work was to investigate the impact of the counter ion on electrostatic
charge of the resultant salts to inform the salt selection process. The experimental results show the
magnitude of charge and polarity of the flurbiprofen salts to be highly dependent on the type of
counter ion selected for the salt formation. Furthermore, particle adhesion to the stainless steel
surface of the shaking container and the salts’ compression properties were measured. The formed
salts had lower electrostatic charges, improved tabletability, and resulted in reduced adhesion of
these powders compared with the parent drug.
Keywords: triboelectrification, electrostatic, salt formation, crystal structure, compaction
1. Introduction
In many instances, physical properties of pharmaceutical powders need to be modified to attain
optimal processing characteristics suitable for formulation design (Wouters and Quéré, 2012).
Various strategies for modifying the physical properties of pharmaceutical materials have been
attempted to address specific drug formulation problems. Crystallising acidic or basic drugs into
salts is a method routinely used in the pharmaceutical industry to enhance the solubility or stability
of drugs and can overcome some undesirable characteristic which exist in the parent drug. Salt
formation can increase the solubility by several orders of magnitude, which has a significant effect
on the dissolution rate of pharmaceutical compounds (Serajuddin, 2007). The increase in solubility
and dissolution rate effectively translates into an increased rate and extent of absorption for the drug
(Elder et al., 2012). An estimated half of all drug molecules used in medicinal therapy are
administered as salts (Stahl and Wermuth 2002). The charged groups of the parent drug and the
counter ion are attracted by intermolecular coulombic force. The salt form is then precipitated and
recrystallised at set conditions to minimise impurities which otherwise may have a significant effect
on the strength of the resulting intermolecular bonds leading to changes in crystal habit.
Consequently, salt formation is often the final stage that determines the physical properties of
primary materials for formulation development. The basis for salt formation generally begins with
the selection of small, compact counterions to enhance solubility (Elder et al., 2012). Additions of
hydrophilic groups to the counter ion can improve solubility, but the additional H-bonding
capability can result in undesirable properties, e.g. polymorphism or hydrate formation (David et
al., 2012), which may result in differences in physicochemical properties of the material (Vrani�,
2003).
However, there is often a compromise to be made between solubility and other physiochemical
properties. Selection of the appropriate solid form is critical both for chemical and pharmaceutical
processing (Kumar et al, 2008) and therefore significant efforts are typically expended into
selecting the optimum salt form for ionisable compounds. The selection process requires a well-
designed screening strategy to ensure various development issues are addressed as early as possible.
The selection process must therefore be rational and streamlined to aid the selection of a suitable
salt as numerous salt forms are available. Alternatively, several salt forms of the drug candidate
may be synthesised for preformulation testing. The selection of the most appropriate salt form does
not necessarily equate to selection of the salt with the optimal solubility and dissolution rate
(Waterman et al., 2002), but rather a balance between best aqueous solubility, degree of
crystallinity, hygroscopicity, melting point, chemical and physical stability and bulk physical
properties (Gould, 1986, Serajuddin, 2007). It is well established that the salt selection strategy and
formulation strategy should be fully aligned (Bastin et al., 2000). The physicochemical properties of
new salt forms are thoroughly characterised in the early stages of drug development and
characterisation commonly includes particle size, particle habit, flow properties etc., however, very
little work is reported on the characterisation of triboelectrification properties of the salt forms.
Particle electrification is a common phenomenon that occurs in many powder handling industries
including pharmaceutical, food and detergent industries. In the pharmaceutical industry the
triboelectrification process refers to a method of particle electrification which can take place during
powder handling operations. The triboelectric charging is regarded as a solid state electrochemistry,
where there is no transport medium (electrolyte) and the reaction depends on a physical contact
(Matsusaka et al., 2010). Therefore, surface modifications due to salt formation are likely to affect
the charge transfer process. Powder handling operations, such as pneumatic conveying, sieving,
mixing and milling, cause particles to make frequent contact amongst themselves and with the walls
of the processing equipment (Šupuk et al., 2012). In these processes, particles are brought into
contact with each other; transfer charges and remain charged upon separation (Greason, 2000). In
many cases, the excessive triboelectrification of powders is problematic: in the extreme, it may lead
to dust explosions, but even at more modest levels, may give rise to segregation of components
(Šupuk et al., 2011) affecting the content uniformity. Furthermore, when materials become charged,
their behaviour can change leading to increased inter-particle cohesion or repelling of other charged
materials (Matsusaka et al., 2010) which has an effect of reducing the flow and creating the
resistance resulting in deposition and blockage of pipes (Matsusaka and Masuda 2003).
In this work a model acidic drug, flurbiprofen, was used. It is a hydrophobic crystalline drug
known to have poor mechanical and adhesion properties, factors which are common for materials
with a great propensity for triboelectrification. Flurbiprofen is a poorly soluble crystalline drug
belonging to the non-steroidal anti-inflammatory (NSAID) class of drugs used to reduce
inflammation and pain relief by targeting a non-selective cyclo-oxygenase (COX) inhibitor, an
enzyme responsible for production of natural inflammatory substances as a reaction to an injury. It
is frequently used in treatment of osteoarthritis and rheumatoid arthritis (Cushny, 2012). However,
the drug does not provide immediate relief of pain due to low aqueous solubility of 0.03 mg/ml
(Morimoto, 1992). It is known to have poor compaction properties (Ramirez, 2010; Chow et al.,
2012), flowability and adhesion properties having a tendency to adhere to the punch surfaces during
compaction (Wang et al., 2004, Serajuddin, 2007, Ramirez, 2010). The poor mechanical and
adhesion properties may be caused by high flurbiprofen charge and diminution of this charge may
lead to improvements in these properties. The drug was used to form a number of salts of varying
properties, with a series of amine counter ions in an equimolar ratio using a suitable solvent.
Successful salt formation was confirmed by an assessment of the salt forms following analytical
characterisation. Triboelectrification properties of the formed salts were investigated using a tribo-
electric device based on a shaking concept. The electric charge transferred to the particles was
quantified by a Faraday cup as a function of shaking time, frequency and container material. The
potential impact on the triboelectrification and compression behaviour of the salt forms was
assessed.
2. Materials and Methods
2.1 Materials
Flurbiprofen, (RS)-2-(2-fluorobiphenyl-4-yl) propanoic acid, contains a biphenyl group and
a fluorine atom at the ortho position of the second biphenyl ring (see Figure 1), has a pKa value of
4.22 (Lacoulonche et al. 1997), melting point of 115 °C and a molecular weight of 244.26 g/mol.
The materials used in this study are listed in Table 1. In addition to the listed materials,
acetonitrile and methanol were used as solvents. The partition coefficient, CLogP, and the acid
dissociation constants, pKa, were obtained from the literature.
2.2 Methods
2.2.1 Salt formation
Flurbiprofen salts were prepared by combining an equimolar ratio (0.01 moles) of the
flurbiprofen with the relevant amine in 40 ml of acetonitrile. The solution was thoroughly mixed
and the precipitate recovered using vacuum filtration. The precipitated salts were oven dried at 50°C
and 300 mbar. The exception was the flurbiprofen tris salt which was made by dissolving the amine
in a warmed solution of methanol before adding to a solution of the drug in acetonitrile. The
resulting solution was kept at -20°C for 20 hours in a freezer until the flurbiprofen tris salt
precipitated; then the crystals were collected by vacuum filtration.
2.2.2 Salt characterisation
The salts were characterised using a variety of analytical techniques including differential
scanning calorimetry (DSC), thermogravimetric analysis (TGA), x-ray powder diffraction (XRPD)
and Fourier transform infrared spectroscopy (FT-IR) to confirm their formation. Particle size
distribution and surface asperities were characterised using Malvern Mastersizer 2000 and Jeol
JSM-6060CV Scanning Electron Microscope (SEM).
2.2.3 Fourier transform infra-red (FR-IR)
The powder in solid form (5-10 mg) was placed on an Attenuated Total Reflection (ATR) plate
and analysed using FT-IR spectroscopy. Salt confirmation was analysed by measuring the
transmittance of infrared wavelengths of the electromagnetic spectrum of the sample in the range of
400 to 4000 cm-1.
2.2.4 Thermal analysis
Differential scanning calorimetry (DSC) was performed using Mettler Toledo DSC. Specimens
(approx. 5 mg) were analysed in vented aluminium pans under dry nitrogen purge (at 50 mL min-1)
over the range 25 to 250°C at 5 °C min-1 heating rate. Thermogravimetric analysis (TGA) was
performed using Mettler Toledo TGA using between 5 and 10 mg of sample over the temperature
range 25 to 250 °C with nitrogen as a purge gas flowing at 200 ml/min.
2.2.5 Powder x-ray diffraction (XRD)
The XRD patterns of drug and salt samples were obtained using Bruker D2 Phaser XRD
diffractometer. The samples were scanned from 5 to 100° 2� at a rate of 1.5° min−1.
2.2.6 Particle size and shape observations
Scanning electron microscopy (SEM) images of the sample surface were obtained using Jeol
JSM-6060CV SEM. The sample surface topography, composition, particle size and other properties
were obtained from the images. Samples were sputter-coated with an ultra-thin coating of
gold/palladium (80:20) for 60 seconds using the Quorum SC7620 Sputter Coater. The ddescription
of particle shape by Rawle (2008) was followed.
2.2.7 Particle size distribution (PSD)
The PSD was determined using laser light scattering technique using Malvern Mastersizer 2000
wet dispersion method. Flurbiprofen salts (0.1% w/v) were dispersed in cyclohexane using
ultrasonication. Igepal CA 30 was used to aid dispersion. Particle size distribution was described
using volume equivalent diameters at 10% (d10), 50% (d50) and 90% (d90) cumulative volume.
2.2.8 True density
The true densities of the drug and salt powders were measured in triplicate using a Helium
Pycnometer (Micrometrics, UK).
2.2.9 Tribo-electrification
A tribo-electric device based on a shaking concept, previously described by Šupuk et al., (2009)
and later by Asare-Addo et al., (2013) was used to investigate the tribo-electrification of bulk
powders by determining the charge-to-mass ratio. Charge-to-mass ratio is an important parameter
that needs to be determined in order to accurately predict the behaviour of charged particles. The
most common device used for charge-to-mass measurement is the Faraday cup, which works on the
principle that charge induces an image of itself on a conducting surface. In this work, the charge-to-
mass ratio of the bulk powders was measured following shaking using a custom made Faraday cup
connected to an electrometer (Keithley Model 6514). A typical Faraday cup is shown
diagrammatically in Fig. 2.
The Faraday cup consists of two conducting cups with an entrance on the top through which
powder can enter. The inner cup is isolated from the outer cup by an insulating spacer. The outer
cup is used to prevent external charges being measured and reduce any external noise. As
demonstrated in Fig. 2, if a positively charged particle enters the Faraday cup, a negative charge (q)
is induced and distributed on the inner surface of the Faraday cup, whilst a positive charge is
distributed over the outer surface of the cup, setting up an electric field and a potential difference
between the two cups.
The capacitance C between the inner and outer cups (Fig. 2) acquires a potential, � = �/�
which is measured by an electrometer connected to an inner cup. The charge-to-mass ratio is
obtained by dividing the net charge measured and the mass of the sample tested. Tests were carried
out under ambient temperature (22 ºC) and humidity (25-45 % RH).
2.2.10 Compression of flurbiprofen and its salts
All the powder samples were compressed using a Testometric M500 - 50 CT (Testometric
Company Ltd., United Kingdom) materials testing machine equipped with 13.00 mm Atlas
Evacuable Pellet Die (Specac Limited, United Kingdom). The powder was accurately weighed (300
± 2 mg) on an analytical balance and poured into the die. Among the flat-faced punches of the
materials testing machine, the lower punch was held stationary while the upper punch moved at a
speed of 3 mm/min during loading and 1 mm/min on unloading. The compacts were fabricated at
applied pressure range between 50 and 250 MPa. Flurbiprofen showed higher degree of capping
and lamination at maximal pressure therefore only two compacts could be made at 250 MPa. After
ejection, the tablets were stored over silica gel for 24 h to allow for elastic recovery. Relative
humidity and temperature during compaction work were in the range 25-45 % RH and 22 �C,
respectively.
Tablets were then fractured diametrically using a Tablet Hardness Tester (Pharma Test PTB
311E). Maximum breaking force, diameter and thickness of compacts were used to calculate tensile
strength according to Equation 1, (Fell and Newton, 1970):
�� = ��� (1)
Where �X is tensile strength (MPa), F is the breaking force (N), D is the tablet diameter (m),
and H is the thickness of tablet (m).
The tablets compressional characteristics were studied using Heckel compression model
(Heckel, 1961; Heckel, 1961a), relating powder porosity (E) during compression to the applied
pressure (P). The equation is written as follows:
� ���� = �� + � (2)
Where K and A are constants representing particle rearrangement and slope of the linear
region, respectively.
The slope of the straight line portion (K) is inversely related to the material’s mean yield
pressure (Py):
�� = �� (3)
The yield pressure (Py) gives an indication regarding the plasticity of the material, so it can
be utilized to classify the compacts from very soft to hard, Table 2. The compression data profiles
were then fitted to the linear form of Kawakita’s equation, (Kawakita and Ludde, 1970-1971) given
by equation 4:
�� =
��� +
�� (4)
Where P is the applied pressure and C is the engineering strain, calculated as,
� = �� − !
(5)
Where Vo is the initial powder volume and V is the volume of the powder at pressure P. The
Kawakita parameters a and b-1 were calculated from the linear regression of the profiles.
3. Results and Discussion
3.1 Thermal Analysis
Thermal analysis was carried out using TGA and DSC techniques. The inclusion of water
within the crystal lattice is known to change the shape, symmetry and number of molecules within
the unit cell (Khankari and Grant, 1995), which may influence the electrostatic behaviour. As a
result, TGA analysis was carried out which showed no weight losses that would indicate
hydrate/solvate formation. The results from DSC are summarised in Table 3 and are in accordance
with previous publications (David et. al., 2012, Schwalbe et al., 2010). The melting points of
resultant salts increased with respect to the parent drug, with the exceptions of the F-Oct salt.
Furthermore, the DSC plot of the F-Tris salt show two characteristic peaks; at 149 °C and 153 °C,
suggesting the possible existence of another polymorphic form (Schwalbe et al., 2010).
3.2 Powder X-ray diffraction analysis
The results from X-ray diffraction studies are shown in Figure 3. Salt formation was confirmed
from differences in the X-ray diffraction patterns between 5°-40° at angle 2�° between the parent
drug and the salt forms. Additionally, the crystallinity of samples which may have a significant role
on the properties of the materials including electrostatic charging due to disorders within the crystal
lattice was evaluated for the salt forms. The peaks in diffraction patterns indicate crystalline
character being retained for all the salts formed. Salts formed using counter ions Benz, Tris, But and
AMP1 produced salts with increased crystallinity as shown by the changes in the corresponding
XRD patterns in Figure 3. Furthermore, the loss of some distinct peaks was observed from
diffraction patterns of F-Benz and F-AMP1 salts. The degree of crystallinity varies between the salt
forms depending on the degree of disorder in the crystal lattice induced by the counter ions during
salt formation.
3.3 Fourier Transform Infra-Red (FT-IR) analysis
Salt formation was also confirmed by analysing FTIR patterns from that of the parent drug and
the salt forms. Flurbiprofen molecule has a signature C=O stretching of the carboxylic acid group at
1684 cm−1which was found to be absent in the salts. This was replaced by bands characteristic of
carboxylic acid salts, at 1650–1550 cm−1 and 1440–1335 cm−1 (David et. al., 2012). An additional
band was present between 3350–3150 cm−1, and is attributable to NH3+ stretching of solid amine
salts (Socrates, 1994).
3.4 Scanning Electron Microscopy (SEM)
The particle shape and morphology of salts formed using different counter ions were analysed
by SEM. As shown in Figure 4 and described in Table 3, addition of different counter ions resulted
in different crystal morphologies. The results showed the salts to have recrystallised mainly with
needle-like morphologies, with the exceptions of F-But, F-Oct and F-Tris which were prism, tabular
and columnar, respectively. All the salts imaged show a tendency of primary particles to aggregate.
3.5 Particle Size Analysis
The particle size results from laser diffraction analysis are summarised in Table 3. The
geometric particle size data indicate that generally the salt forms are noticeably larger in size than
the parent drug. The exception is F-Oct salt which had smaller particle size distribution and span of
1.8 identical to the parent drug. The data also indicate differences between the salt forms with those
crystallised using Benz and Tris counter ions containing a higher proportion of fines. The results
indicate that F-Chex and F-Tbut salts, as well as F-AMP1 and F-Tris salts, have similar particle size
distributions. Furthermore, F-Benz, F-Chex, F-Tbut and F-AMP1 show bimodal distribution with
some larger particles present possibly due to materials being needle shaped.
3.6 Triboelectrification
In the initial stage of the test procedure the initial charge of a sample was measured and
indicated as time 0 in Fig. 5. The initial charge represents the charge first measured from the
powder before being subjected to the tribo-electrification process. Figure 5 shows the charge
measurements for flurbiprofen at the following time intervals; 0.5, 2, 5 and 10 minutes. The data
points plotted on the graph are the result of at least three independent measurements. The
flurbiprofen powder charged negatively against the stainless steel surface at each time interval.
It was found that the electrostatic charge increased with the shaking time and reached a
maximum charge (-226 nC g-1) after 5 minutes of tribo-charging. Following this stage, there was a
reduction in the charge level as the tribo-charging time is increased. This is referred to as the
saturated charge level and represents the amount of charge generated from particle impacts after
which no further increase in charge occurs. Making assumptions centred on the current
observations, it is reasonable to predict that unless the powder is neutralised, it is unlikely that the
charge will ever reach a zero value beyond 10 minutes of tribo-charging, due to the powder
particles interacting along the walls of the container during shaking. The frequency of shaking was
kept constant as changes in frequency would affect the number of shaking cycles which, in turn,
may affect the particle-wall collisions altering the charge relaxation time between successive
impacts.
The charge of flurbiprofen salts was also characterised at 0.5, 2, 5 and 10 minutes. The saturated
charge levels of the salt forms are shown in Fig. 6. For comparison purposes results for flurbiprofen
are also added to Fig. 6. The results show that salt formed using counter ions AMP1, Benz, Tris,
Oct and But resulted in samples charging negatively against the stainless steel surfaces in line with
the polarity of the parent drug. In contrast, the salts formed using Tbut and Chex counter ions had
electro positive charge against the stainless steel container. The level of charge on salt formed using
AMP1 counter ion was considerably higher than all the samples tested including the parent drug.
This level of charge was sufficient to cause processing problems i.e. increased particle adhesion to
the stainless steel surfaces (Fig. 5).
The data presented in Table 3 highlight the importance of understanding the implications of
forming salts using different counterions. F-Tris and F-AMP1 salts have similar saturated solubility.
However, from the triboelectrification data it is evident that there is a significant difference in the
chargeability of the two salts. This is likely to be due to their propensities for hydrogen bonding
which significantly affects the crystal structure of the salts as revealed by structural analysis.
Crystal structures (Schwalbe et al., 2010) of F-Tbut, F-AMP1 and F-Tris were analysed using GDIS
visualisation software (Fleming and Rohl, 2005). Hydrogen bonding functionality of the amine
counterions used was varied by changing methyl groups to hydroxymethyl starting with Tbut as the
initial molecule (0), and increasing the number of hydroxymethyl groups in AMP1 (1) and Tris (3).
Unit cell dimensions of the resultant salts are shown in Table 4 with packing diagrams presented in
Figs. 7-9. From the structural analysis the –OH groups play a significant role in determining the
overall crystal structures. F-Tbut, which has no OH groups present, has an almost triclinic like
crystal shape (Fig. 7) that is quite similar when the Tbut is replaced with AMP1 (Fig. 8). However
with Tris as the base the crystal tends towards an orthorhombic like crystal lattice (Fig. 9). The
intermolecular distances (Table 4) also reflect significant twist particularly for the O1-H1B and the
F1-F2 and F1-H8 distances. The decrease in the O2-O3 distances indicates that the –OH groups are
closer to the –COO group of the flurbiprofen increasing the number of H-bonds within the crystal
allowing the F-Tris salt to be a close-packed structure. The O1-H4 intermolecular distance clearly
identifies significant twisting of the molecules in F-Tris than in F-Tbut. The intermolecular angles
(Table 4) highlight this further where the angles obtained suggest a much more compact packing of
the F-Tris molecules supporting the overall change in the crystal shape and symmetry.
The results show that varying the number of -OH groups on a counterion is sufficient to
influence particle crystal habit resulting in a close-packed structure in F-Tris compared to F-AMP1
salt. Measurement of the electrostatic charge of the salts, following surface modification is expected
to change the effective value of the work functions, influencing the direction of charge transfer
during particle contact. The charge of F-AMP1 is ranked in the upper level of the chargeability
series (Supuk et al. 2011). The level of charge on F-AMP1 is sufficient to cause problems during
formulation processing. Furthermore, F-But and F-Tbut salts have identical physicochemical
properties however, the tendency to charge against stainless steel with an opposite polarity was
observed. This study demonstrates the importance of understanding triboelectrification phenomenon
in an early stage development as a useful tool in the salt selection process.
3.7 Adhesion results
The corresponding adhesion values recorded at the time intervals from Fig. 5 are shown in Figs.
10 and 11. The adhesion is the mass of powder which remained on the walls and was not removed
when the powder was poured into the Faraday cup. Initially the container walls were free from any
adhered particles, but on shaking the particles interact with the surface walls and become highly
charged. These highly charged particles then adhere to the inner walls of the container, forming a
thick layer predominantly at both ends and the bottom of the shaking container. The adhesion
tendency follows that of the charging trend shown in Fig. 5, whereby there is an initial increase in
adhesion up to the saturation level, after which a slight decrease is observed. As the tribo-charging
time is increased post-saturation point, the free moving particles interact mainly with the
concentrated wall-adhered particles instead of the surface of the container. This results in the
majority of the particles interacting with each other as opposed to particle-wall interactions. This
has the effect of slightly reducing the charge of the wall-adhered particles.
Figure 11 shows the mean percentage of adhesion for flurbiprofen and its salt forms
corresponding to the saturated charge level given in Fig. 6. The parent drug had the highest
adhesion in the stainless steel container. The salt formed using t-but counter ion had the smallest
adhesion. The adhesion of particles to the walls can have a significant effect on the generated
charge. The particles which adhere to the wall surfaces may change the charging process from
particle-wall contacts to particle-particle contacts and this may result in the change of polarity of the
overall powder sample. Particles formed following salt formation had varying shapes and surface
asperities. Changing particle shape may alter the proportion of the functional groups present at the
crystal surface and is likely to influence the polarity and magnitude of electrostatic charge.
Furthermore, particle surface asperities affect the surface area available for charge transfer and
serve as a physical separation that may also affect particle adhesion tendency.
3.8 Compression results
In the present study, different salts of flurbiprofen exhibit a monotonically increasing trend in
tablet tensile strength (�X) with regards to pressure. All the salts show improved tabletability
compared with the parent drug. Among the salts, F-AMP1 showed highest tablet tensile strength
(�X), while F-Tbut showed the lowest (Fig. 12). The order of the tablet strength from strongest to
weakest is as follows: F-AMP1 > F-Tris > F-Chex > F-Benz > F-But > F-Tbut > F-Oct > FBP.
The mean yield pressure (Py), is inversely proportional to the ability of powder particles to
deform under specific applied pressure. F-Tris has the highest Py however having little difference
with F-AMP1, while the parent drug, flurbiprofen has the lowest Py value. On the basis of the Py
values, these materials can be classified into four categories (Table, 2). The parent drug and F-Tbut
can be described as soft, F-Chex, F-Benz, F-Oct and F-But as moderately hard whilst F-Tris and F-
AMP1 can be classified as hard materials. The plastic deformation trend was therefore as follows:
Soft materials materials> Moderate hard materials >Hard materials.
Kawakita parameters a and b-1 were calculated from the linear regression of the profiles and the
data fit well with having high correlation coefficients (R2> 0.99). It has been established, b-1 is
opposite to the plastic deformation of a material during the compression cycle (Nordströmet al.,
2009; Odeku and Itiola, 1998). In the present study, F-Tbut and flurbiprofen showed the fastest
onset of plastic deformation, which might result in lamination and capping during compression.
However there are some salts (F-Chex, F-Benz, F-But and F-Oct), which plastically deform with
relatively fast rate due to low b-1. F-AMP1 and F-Tris salts show a high plastic deformation with
slow rate (Table 3). Research is in progress to understand the crystal structure of the salt forms and
the effect of orientation of molecular groups at individual surfaces will allow charge transfer
mechanisms to be elucidated. Furthermore, the presence of slip planes in crystal structure may
affect charge transfer which is based on a high impaction process by allowing slipping of one layer
over an adjacent one. In this instance, the charging mechanism would reflect the surface charge of
these planes, unless the slip planes are strengthened by hydrogen bonding or cross-linked by a high
number of van der Waals forces to prevent such slippage.
4. Conclusions
The results show that the type of counter ion selected produces significant differences in the
particle morphology. In turn, it is suggested that these differences influence the work function of the
materials, which has been shown to greatly affect the electrostatic behaviour. Changes in the crystal
habit have been shown to modify the electrostatic properties of the salt forms due to different
arrangements of the atoms in the structures. In some instances, salt formation causes significant
surface modification in comparison to the parent drug, affecting triboelectrification, adhesion and
compaction properties. Thus, the molecular structure of the counter ion has a significant effect on
the particle morphology highlighting the importance of counter ion selection as a precursor to
determining electrostatic behaviour.
The electrostatic charge of the resultant salts shifted in positive direction with F-AMP1
having the highest charge in the order: F-AMP1 > F-Benz >F-Tris> F-Oct > F-But > F-Tbut > F-
Chex. The parent drug had a great propensity for tribo-electric charging. The net charge of the
resultant salts was shown to be lower than that of the parent drug regardless of the type of counter
ion used. The exception was F-AMP1, which charged to a higher level than the parent drug and
sufficiently high to cause problems during formulation and drug development. In general, the salts
formed had a negative charge against the stainless steel surface. It can therefore be assumed that
electrons are being transferred from the stainless steel surface to the powder particles (charging
them negatively), with the exception of F-Chex and F-Tbut which had an electropositive charge.
The salts of flurbiprofen also show different mechanical behaviour during and after compression
experiments. Addition of hydroxymethyl groups in F-AMP1 and F-Tris salts resulted in more
compact packing with strongly hydrogen bonded layers which facilitated inter-particle adhesion
producing stronger compacts.
The triboelectrification methodology used in this work is a sensitive tool able to detect
magnitude of charge at the nano Coulomb level, which is an added advantage when other
techniques are not able to differentiate between physical properties of the salt forms. Successfully
incorporating the triboelectrification methodology, alongside other techniques may lead to a better
understanding of the screening strategy to aid the selection of an optimal salt form and thereby
reducing the likelihood of several salt forms of a drug candidate being manufactured for
preformulation testing.
Acknowledgements
The authors would like to acknowledge University of Huddersfield for financial support and
Faiyadh Mohsan Alshammari and Chen Liu for their help with the data collection.
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